title: Beta-adrenergic signaling in the development and progression of pulmonary and pancreatic adenocarcinoma.
abstract: Small airway epithelial cells from, which most pulmonary adenocarcinomas (PACs) derive, and pancreatic duct epithelia, from which pancreatic ductal adenocarcinomas (PDACs) originate, share the ability to synthesize and release bicarbonate. This activity is stimulated in both cell types by the α7nicotinic acetylcholine receptor (α7nAChR)-mediated release of noradrenaline and adrenaline, which in turn activate β-adrenergic receptor (β-AR) signaling, leading to the cAMP-dependent release of bicarbonate. The same signaling pathway also stimulates a complex network of intracellular signaling cascades which regulate the proliferation, migration, angiogenesis and apoptosis of PAC and PDAC cells. The amino acid neurotransmitter γ-aminobutyric acid (GABA) serves as the physiological inhibitor of this cancer stimulating network by blocking the activation of adenylyl cyclase. This review summarizes experimental, epidemiological and clinical data that have identified risk factors for PAC and PDAC such as smoking, alcoholism, chronic non neoplastic diseases and their treatments as well as psychological stress and analyzes how these factors increase the cancer-stimulating effects of this regulatory cascade in PAC and PDAC. This analysis identifies the careful maintenance of balanced levels in stimulatory stress neurotransmitters and inhibitory GABA as a key factor for the prevention of PDAC and suggests the marker-guided use of beta-blockers, GABA or GABA-B receptor agonists as well as psychotherapeutic or pharmacological stress reduction as important tools that may render currently ineffective cancer intervention of PAC and PDAC more successful.
authors.affiliation: Experimental Oncology Laboratory, Department of Biomedical & Diagnostic Sciences, College of Veterinary Medicine, University of Tennesse, Knoxville, TN, USA.
authors.forename: Hildegard M
authors.initials: HM
authors.lastname: Schuller
authors.forename: Hussein A N
authors.initials: HA
authors.lastname: Al-Wadei